Chief Complaint: 41-year-old female with 2-month history of persisting and recurrent keratitis in her right eye (OD).

History of Present Illness: This soft contact lens user initially presented to her local ophthalmologist with pain, photophobia, and decreased vision in the right eye in July of 2005. She was found to have a geographic ulcer and herpes simplex virus (HSV) was suspected. She was initially treated with Trifluridine (Viroptic) eye drops and oral Acyclovir, followed by Loteprednol (Lotemax) topical steroid drops four days later. However, when epithelial disease recurred, the steroid drops were stopped and cultures of the ulcer were taken. Cultures eventually grew fungus identified as a fusarium species. Though the patient was started on Amphotericin B eye drops and oral Fluconazole, the corneal ulcer was difficult to heal. After initial improvement on this regimen, the epithelium again broke down and the corneal ulcer deepened. Repeat culture again confirmed a fusarium species of fungus. The patient was referred to the University of Iowa Department of Ophthalmology for evaluation and care.

Upon presentation at the University of Iowa, the patient complained of blurry, decreased vision and pain in her right eye.

Past Ocular History: No prior ocular surgery or trauma. The patient had worn soft contact lenses since the 8th grade, though she denies sleeping or swimming in her contact lenses.

Course: Repeat corneal cultures were performed upon presentation to the University of Iowa for probable fungal keratitis. Confocal microscopy was also performed on the day of presentation, revealing hyphal elements deep in the stroma, consistent with filamentous fungi. The patient was treated with combination therapy of Natamycin 5% every 2 hours around the clock and Voriconazole 200mg oral therapy twice a day. Mydriatic drops were given for comfort. Corneal culures did grow Fusarium species.

Three weeks after presentation, the patient was also give subconjunctival injections of Fluconazole (2mg/1ml, 1.0cc) and then Amphotericin B (1mg/0.5ml, 0.5cc) with some initial improvement. However, despite agressive antifungal therapy for several weeks, the central cornea continued to become thinner and central scarring significantly reduced vision in the right eye (see Figure 3). In December 2005, the patient underwent full-thickness penetrating keratoplasty (PKP) of the right eye. Intraoperatively, 5ug injections of Amphotericin B were injected into the anterior chamber both before PKP and after placement of the graft. An additional 2.0mg of Amphotericin B was injected in the subconjunctival space at the conclusion of the case.

At first, the patient recovered well from the surgery and maintained a clear anterior chamber and corneal graft tissue on topical Natamycin and oral Fluconazole. However, within a two weeks, recurrent corneal infiltrate began to develop at the inferior graft-host junction, followed by the development of cells and hypopyon in the anterior chamber. The patient underwent repeat PKP one month after her first surgery. Periodic Acid-Schiff (PAS) and Gomori methenamine silver (GMS) stains of the excised corneal button confirmed the recurrence of branching hyphal elements. Culture of the excised tissue again grew Fusarium.

After the second PKP, the patient slowly recovered on frequent topical Voriconozole, increased oral Voriconazole, and injections of subconjunctival and intracameral Amphotericin B on two occasions. As the patient was tapered off of antifungal therapy over the ensuing 60 days, there was no evidence of recurrent fungal infection. One episode of early graft rejection was treated successfully with intravenous and topical steroids.

By summer of 2006, the patient's cornea was quiet, selective suture removal had begun, and the patient was able to be refracted to 20/20-. The patient was myopic with astigmatism of approximately 1 diopter remaining. With the assistance of the Contact Lens service at the University of Iowa, the patient was fit with a Dyna Intra-Limbal® rigid contact lens which allowed 20/20 visual acuity. The patient is off all antifungal medications and on maintenance topical steroid in the right eye. There is no evidence of fungal recurrence.

Discussion: In the United States, fungal keratitis is far less common than bacterial keratitis (5-10% of reported cases). The most common cause of fungal keratitis is ocular injury from sticks or other vegetable matter. Immunosuppression (especially topical corticosteroids which reduce resistance to infection) also increases the risk of fungal keratitis. Patients who wear contact lenses are also more likely to develop fungal keratitis. Fungi are more prevalent in moist, subtropical and tropical climates. Worldwide, Aspergillus species are the most common cause of bacterial keratitis (Foster CS, 1992), whereas in the United States, Candida species are also frequently isolated. In the subtropical climate of the American Southeast, Fusarium species are the most common fungal keratitis pathogen (Jones DB, 1970). However, there has recently been a dramatic increase in fungal keratitis from Fusarium species even in temperate climates that has been associated with contact lens wear and specific contact lens solution that deserves further discussion.

Fusarium keratitis: The increase in Fusarium keratitis was first described by the Singapore Minstery of Health in February of 2006 (Ministry of Health Singapore, 21 Feb 2006), and a peer-reviewed paper reviewing 66 cases of Fusarium keratitis associated with the ReNu®contact lens solutions (ReNu, Bausch & Lomb, Rochester, NY) was later published in the Journal of the American Medical Association (Khor WB, et al, 2006). During this same time period, similar cases from around the United States were being reported, the vast majority of which were associated with a specific contact lens solution (ReNu® with MoistureLoc), prompting Dr. Douglas C. Chang, M.D., of the Centers for Disease Control and Prevention (CDC) in Atlanta, and his colleagues to conduct a study to determine which specific activities, contact lens products, or hygiene practices may be associated with the rising Fusarium keratitis outbreak. Gathering data on cases from June of 2005, the team identified 164 confirmed Fusarium keratitis cases in 33 states and 1 U.S. territory, including cases from the Midwestern states treated at the University of Iowa. Ninety-four percent of the confirmed case patients wore soft contact lenses. Compared with neighborhood-matched controls, the patients with Fusarium keratitis were over 20 times more likely than controls to report using ReNu® with MoistureLoc, while the reported use of other contact lens solutions (including other ReNu® products) was similar between case patients and controls (Chang DC, et al, 2006). Related investigation of the Bausch & Lomb production (Greenville, SC) and storage locations, solutions, and unopened solution bottles did not reveal an active source of the fungus. The production lots implicated in the outbreak were not clustered in time. Though the exact cause for the infections is not known, it is hypothesized that an interaction between one of the solution ingredients with the Fusarium may have allowed the organism to grow more readily. Additional studies are still underway.

Upon initiation of the CDC study, Bauch & Lomb voluntarily withdrew the ReNu® with MoistureLoc product from the market, and a global recall of the solution was later issued on May 11, 2006 (FDA Statement). Concerned ophthalmologists have used both the lay press and scientific publication to warn the public and practitioners about this association and the solution recall (Indiana, Iowa, US Dept Health and Human Services). However, serious vision-threatening cases of Fusarium keratitis continue to present at the University of Iowa associated with the use of the implicated contact lens solution by patients who are unaware of the product recall.

Presentation: In general, fungal keratitis has a more indolent presentation as compared to most bacterial corneal infections. With fungal keratitis, the patient is more likely to have a mild foreign body sensation and minimal conjunctival injection initially. Increasing pain and inflammation will often develop, though it may take several days. With time, fungal keratitis can become just as inflammed, injected, and suppurative as comparable bacterial infections, especially with incomplete antimicrobial coverage.

On examination, fungal keratitis may have the same signs as other forms of infectious keratitis including injection, epithelial damage, white or creamy stromal infiltrates, suppurative discharge, and anterior chamber cells, fibrin, or hypopyon. However, unlike most cases of bacterial keratitis, fungal disease may often have branching ulcers, feathery edges to the infiltrate, satellite lesions, or elevations in the cornea. There may be elevated lesions on the cornea and a dry, rough texture evident with examination or culture. And yet, these suggestive findings are not always present, and when they are it is not necessarily pathognomonic for fungal keratitis. In fact, practitioners are not usually able to distinguish between bacterial and fungal disease on the basis of clinical findings alone (Sevel D, Kassar B 1973). Given this, the ophthalmologist must make routine use of cultures, smears, corneal scrapings for histopathology, and/or in-vivo confocal microscopy to obtain an accurate diagnosis and guide appropriate therapy. Confocal microscopy may be helpful to provide quick, non-invasive information early in the course of disease to reveal the presence of fungal elements (Kaufman SC, 2004). At the University of Iowa, we routinely use tandem scanning and scanning slit confocal microscopy as an additional adjunctive diagnostic tool that can, in some cases, provide highly informative images of branching hyphae (see Figure 2), budding yeast, or acanthamoeba (Winchester K, et al, 1997, and Winchester K, et al, 1995). Further study of the applications of this relatively new diagnostic tool is needed.

Treatment: Fusarium is usually susceptible to the polyenes (Amphotericin, Natamycin), and the Azole antifungals Econazole and Ketoconazole (Benson WH, Lanier JD, 1992). Microbiology studies in Florida, where Fusarium species are more endemic, further indicate susceptibility to Natamycin (range 0.15-5, mean 1.5ug/ml) and Amphotericin (0.078-5, mean 1.2 ug/ml) topically with variable susceptibility to the azoles (i.e. Ketaconazole, Miconazole) (Rosa RH, et al, 1994). Recent studies have also shown that some pyrimidines (especially Voriconazole) may also be used with success (as was the case in our patient) (Marangon FB, et al, 2004; Klont, et al, 2005), though some in vitro studies have suggested intermediate susceptibility. Natamycin 5% is commercially available in the United States, whereas Amphotericin B must be prepared in the pharmacy. As such, Natamycin is often used as initial therapy in the United States (Jones DB, et al, 1970 and Jones DB, 1972). However, the practitioner must be aware in treating Fusarium keratitis that Natamycin is known to have significant ocular toxicity as a side effect and this can confound the picture when observing treatment effect over time. The practitioner must also be aware that the corneal epithelium is a natural barrier to the penetration of many topical antifungal agents and epithelial debridement, especially early in the course of treatment, may be indicated to improve antifungal effect. Unfortunately, despite aggressive and appropriate anti-fungal treatment, the infection may still be difficult to extinguish. Treatment course may be lengthy, averaging 39 days in one study (Jones DB, 1970), though there is no firmly established treatment criteria. Even with eradication of the fungus, visually significant scarring may result. A full third (34%) of the patients reviewed by Dr. Chang and the CDC team required corneal transplantation (Chang DC, et al. 2006).

Diagnosis: Fungal keratitis (Fusarium species)

EPIDEMIOLOGY

Fungal keratitis represents 5-10% of reported cases of keratitis

Fungal keratitis is more common in tropical and subtropical climates (may be up to 20% of keratitis in Southeastern U.S.)

Aspergillus species is most common cause of fungal keratitis worlwide

Aspergillus sp. and Candida sp. are most frequently isolated in the United States

Routine culture media should be used to identify the causative organism, as most fungi grow well in blood agar or Sabouraud dextrose agar

Scraping of the epithelium provides a good sample for histopathologic samples and may improve penetration of antifungal agents

In some cases, corneal biopsy may be required

SYMPTOMS

Usually more indolent presentation than bacterial keratitis

Patient may initially have only foreign body sensation with gradually increasing pain

Patients may also have photophobia, tearing, and more severe pain

TREATMENT

Frequent, topical antifugal drops are the principal drugs used to treat fungal keratitis

Polyenes
- good sensitivity in vitro and in clinical studies

Natamycin 5% is commercially available and often used as a initial drug of choice for fungal keratitis

Amphotericin (usually 0.15%) is especially effective against yeasts and Aspergillus species and is recommended in most sources (the addition of flucytosine may provide a synergistic effect in difficult cases)

Miconazole is the drug of choice for the rare cases of fungal keratitis caused by Paecilomyces sp.

Pyrimidines - (Voriconazole and Itraconazole)

Voriconazole, topical and oral, is a new option that shows promise against Fusarium sp. (as in this patient)

Mechanical debridement of the corneal epithelium may aid in penetration of topical medication into the stroma while providing a specimen for histopathological stains and evaluation

Therapeutic penetrating keratoplasty is often required to restore vision impairment due to corneal scarring

Early transplant during active disease ("hot PKP") may be required early in cases of perforation or near-perforation or when there is progressive deep stromal disease despite maximum pharmacologic therapy